Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire

Viret, Christophe; Lamare, Camille; Guiraud, Martine; Fazilleau, Nicolas; Bour, Agathe; Malissen, Bernard; Carrier, Alice; Guerder, Sylvie

doi:10.1084/jem.20100027

Cited by 43 publications

(38 citation statements)

References 25 publications

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“…In a parallel study in the NOD mouse, likewise, we found that Tssp is required for the development of CD4 T cells specific for 1 foreign protein Ag (hen egg lysozyme [HEL]) out of 6 tested (30). In this case too, impaired development of the corresponding functional CD4 TCR repertoire could be induced by Tssp° DCs, likely through presentation of an HEL-mimotope of sufficient affinity to delete HEL-reactive CD4 T cells.…”

Section: Figurementioning

confidence: 84%

“…The above results suggested that the diabetes resistance of Tssp° NOD mice is a property of conventional CD4 T cells. Since thymic expression of Tssp is necessary for the development of some class II-restricted TCRs (11,30), we considered the possibility that Tssp may likewise control the intrathymic selection of some islet-specific CD4 T cells, and, thus, its absence may introduce some holes in the autoreactive T cell repertoire. We therefore analyzed the response of Tssp° and WT control NOD mice to the immunodominant peptide of known islet autoantigens suspected to play a role in diabetes development (16).…”

Section: Figurementioning

confidence: 99%

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Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Viret¹,

Leung–Theung–Long²,

Serre³

et al. 2011

J. Clin. Invest.

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Type 1 diabetes is a chronic autoimmune disease in which genetic predispositions affect the immune system, leading to a loss of T cell tolerance to β cells and consequent T cell-mediated destruction of insulin-producing islet cells. Genetic studies have suggested that PRSS16 is linked to a diabetes susceptibility locus of the extended HLA class I region in humans. PRSS16 encodes what we believe to be a novel protease, thymus-specific serine protease (TSSP), which shows predominant expression in thymic epithelial cells and is suspected to have a restricted role in the class II presentation pathway. Consistently, Tssp is necessary for the intrathymic selection of few class II-restricted T cell receptor specificities in B6 mice. To directly assess the role of Tssp in autoimmune diabetes, we generated Tssp-deficient (Tssp°) NOD mice. While remaining immunocompetent, Tssp° NOD mice were protected from diabetes and severe insulitis. Diabetes resistance of Tssp° NOD mice was a property of the CD4 T cell compartment that is acquired during thymic selection and correlated with an impaired selection of CD4 T cells specific for islet antigens. Hence, in the NOD mouse, Tssp is a critical regulator of diabetes development through the selection of the autoreactive CD4 T cell repertoire.

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Section: Figurementioning

confidence: 84%

Section: Figurementioning

confidence: 99%

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Viret¹,

Leung–Theung–Long²,

Serre³

et al. 2011

J. Clin. Invest.

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“…The initial positive selection of the randomly generated TCR repertoire by cTEC critically depends on the expression, processing, and presentation of a diverse set of self-peptides (Starr et al 2003; Cold Spring Harbor Laboratory Press on August 27, 2018 -Published by genome.cshlp.org Downloaded from Klein et al 2009;Viret et al 2011). The repertoire of self-peptides presented by cTEC is also of interest because these cells contribute to negative selection (Ahn et al 2008;McCaughtry et al 2008;Stritesky et al 2013), and the generation of T reg (Liston et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

et al. 2014

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Promiscuous gene expression (PGE) by thymic epithelial cells (TEC) is essential for generating a diverse T cell antigen receptor repertoire tolerant to self-antigens, and thus for avoiding autoimmunity. Nevertheless, the extent and nature of this unusual expression program within TEC populations and single cells are unknown. Using deep transcriptome sequencing of carefully identified mouse TEC subpopulations, we discovered a program of PGE that is common between medullary (m) and cortical TEC, further elaborated in mTEC, and completed in mature mTEC expressing the autoimmune regulator gene (Aire). TEC populations are capable of expressing up to 19,293 protein-coding genes, the highest number of genes known to be expressed in any cell type. Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-restricted genes. Notably, the tissue specificities of these genes include known targets of autoimmunity in human AIRE deficiency. Led by the observation that genes induced by Aire expression are generally characterized by a repressive chromatin state in somatic tissues, we found these genes to be strongly associated with H3K27me3 marks in mTEC. Our findings are consistent with AIRE targeting and inducing the promiscuous expression of genes previously epigenetically silenced by Polycomb group proteins. Comparison of the transcriptomes of 174 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low cell frequency. Furthermore, when present, Aire expression-dependent transcript levels were 16-fold higher, on average, in individual TEC than in the mTEC population.

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“…The TCRα and TCRβ nomenclatures were previously defined by Lee et al and Wilson et al, respectively (Lee IY, 1998, unpublished; [37]) and are available at www.imgt.org. For CDR3 sequencing, the PCR reaction was made using Phusion TM High-Fidelity DNA polymerase (Thermo Scientific) and the appropriate Vα or Vβ sense primers together with Cα or Cβ anti-sense primers, as previously described [38].…”

Section: Facs Staining and Ed 50 Determination Of S100β 1-15 -Specifimentioning

confidence: 99%

Central tolerance spares the private high‐avidity CD4⁺ T‐cell repertoire specific for an islet antigen in NOD mice

2015

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Although central tolerance induces the deletion of most autoreactive T cells, some autoreactive T cells escape thymic censorship. Whether potentially harmful autoreactive T cells present distinct TCRαβ features remains unclear.Here, we analyzed the TCRαβ repertoire of CD4 + T cells specific for the S100β protein, an islet antigen associated with type 1 diabetes. We found that diabetes-resistant NOD mice deficient for thymus specific serine protease (TSSP), a protease that impairs class II antigen presentation by thymic stromal cells, were hyporesponsive to the immunodominant S100β 1-15 epitope, as compared to wild-type NOD mice, due to intrathymic negative selection. In both TSSP-deficient and wild-type NOD mice, the TCRαβ repertoire of S100β-specific CD4 + T cells though diverse showed a specific bias for dominant TCRα rearrangements with limited CDR3α diversity. These dominant TCRα chains were public since they were found in all mice. They were of intermediate-to low-avidity. In contrast, high-avidity T cells expressed unique TCRs specific to each individual (private TCRs) and were only found in wild-type NOD mice. Hence, in NOD mice, the autoreactive CD4 + T-cell compartment has two major components, a dominant and public low-avidity TCRα repertoire and a private high-avidity CD4 + T-cell repertoire; the latter is deleted by re-enforced negative selection.Keywords: Autoimmunity r Avidity r CD4 + T cells r NOD r TCR repertoire r T-cell tolerance Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionClonal deletion in the thymus is a major mechanism establishing T-cell tolerance to self-antigens (Ag). The seminal demonstration of ectopic expression of peripheral tissue Ags (TSA) by thymic APCs provided the mechanistic basis for the deletion of T cells specific for a large number of TSA [1,2]. Central tolerance is incomplete, however, and it has been estimated that thymic deleCorrespondence: Dr. Sylvie Guerder e-mail: Sylvie.guerder@inserm.fr tion may spare up to 25-40% of positively selected T cells [3]. It is well established that most of these self-reactive T cells show relatively low avidity for their cognate ligand, yet little is known regarding the specific features of their TCRαβ repertoire notably for polyclonal T cells specific for TSA.To further characterize how negative selection shapes the TCR repertoire of T cells reacting to TSA we analyzed the specific features of CD4 + T cells specific for an islet-Ag in conventional NOD mice and NOD mice with reinforced central deletion. The peripheral T-cell repertoire of NOD mice is highly autoreactive and includes CD4 + T cells specific for a large number of islet Ags [4]. This accumulation of islet-reactive CD4 + T cells results, at C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1946-1956 Cellular immune response 1947 least in part, from defects in central tolerance mainly linked to defects in apoptosis induction [5][6][7][8]. Defects in c...

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Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire

Abstract: Thymus-specific serine protease expression in stromal as well as hematopoietic cells in the thymus is needed for diversification of the endogenous repertoire of TCRs specific for a particular protein antigen.

Cited by 43 publications

References 25 publications

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

Central tolerance spares the private high‐avidity CD4⁺ T‐cell repertoire specific for an islet antigen in NOD mice

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Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire

Abstract: Thymus-specific serine protease expression in stromal as well as hematopoietic cells in the thymus is needed for diversification of the endogenous repertoire of TCRs specific for a particular protein antigen.

Cited by 43 publications

References 25 publications

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

Central tolerance spares the private high‐avidity CD4+ T‐cell repertoire specific for an islet antigen in NOD mice

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Central tolerance spares the private high‐avidity CD4⁺ T‐cell repertoire specific for an islet antigen in NOD mice